urb-597 and Pruritus

Itch and pain are two irritating sensations sharing a lot in common. Considering the antinociceptive effects of blockade of endocannabinoid degrading enzymes in pain states, we attempted to reduce scratching behavior by endocannabinoid modulation, i.e. by inhibiting fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), or cellular uptake of endocannabinoids. Scratching behavior was induced by intradermal injection of serotonin to Balb/c mice. URB597 (10 mg/kg, i.p.), a FAAH inhibitor, JZL184 (16 mg/kg, i.p.), a MAGL inhibitor, and AM404 (10 mg/kg, i.p.), an endocannabinoid transport inhibitor, were given to evaluate the effects of endocannabinoid modulation on scratching responses. Then, the CB1 receptor antagonist, AM251 (1 mg/kg, i.p.), and the CB2 receptor antagonist, SR144528 (1 mg/kg, i.p.), were administered to determine whether cannabinoid receptors mediate these effects. URB597 and JZL184, but not AM404, attenuated serotonin-induced scratches. The inhibitory effect of URB597 was reversed by SR144528, but cannabinoid receptor antagonists had no other effects on modulation by the inhibitors. We propose that augmenting the endocannabinoid tonus by inhibition of degradative enzymes, FAAH and MAGL, but not cellular uptake, may be a novel target for the development of antipruritic agents.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Benzodioxoles; Camphanes; Carbamates; Endocannabinoids; Enzyme Inhibitors; Male; Mice; Mice, Inbred BALB C; Monoacylglycerol Lipases; Piperidines; Pruritus; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Serotonin

Pruritus (itch) is a common cause of discomfort by dermatological disorders. Several peripherally and centrally mediated pathologies that induce pruritus do not generally respond to typical allergenic and anti-inflammatory treatments. In accordance, we employed an acute allergenic murine model to determine whether the endogenous cannabinoid system could be targeted to treat pruritus. Subcutaneous administration of the mast cell degranulator compound 48/80 evoked an intense, concentration-dependent scratching response. Systemic Delta(9)-tetrahydrocannabinol reduced the scratching response, although this effect was accompanied with hypomotility. Complementary genetic and pharmacological approaches to target fatty acid amide hydrolase (FAAH), the primary enzyme responsible for the degradation of the endocannabinoid anandamide, were evaluated in the compound 48/80 model. FAAH(-/-) mice and mice treated with the respective irreversible and reversible FAAH inhibitors, URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) and OL-135 [1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane], displayed comparable reductions in scratching to mice treated with common nonsedative allergenic treatments (loratadine and dexamethasone) but without affecting locomotor behavior. The antiscratching phenotype of FAAH-compromised mice was completely blocked by either genetic deletion or pharmacological antagonism of the CB(1) receptor. Neural-specific conditional FAAH knockout (FAAH-NS) mice, which have FAAH exclusively restricted to neural tissues, showed a similar magnitude of scratching as wild-type mice. It is important that URB597 reduced compound 48/80-induced scratching in FAAH-NS mice, but it did not produce any further reduction in FAAH(-/-) mice. These findings indicate that neuronal FAAH suppression reduces the scratching response through activation of CB(1) receptors. More generally, these are the first preclinical data suggesting that FAAH represents a novel target to treat pruritus without eliciting overt side effects.

Topics: Amidohydrolases; Animals; Antipruritics; Behavior, Animal; Benzamides; Cannabinoid Receptor Modulators; Carbamates; Cell Degranulation; Dermatitis, Contact; Dose-Response Relationship, Drug; Dronabinol; Endocannabinoids; Enzyme Inhibitors; Genotype; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; p-Methoxy-N-methylphenethylamine; Pruritus; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid